Tetrahydropyridine-(or 4-hydroxypiperidine) alkylazoles

ABSTRACT

The present invention relates to the compounds of general formula                    
     used as medicaments possessing therapeutic activity for the treatment of anxiety, psychosis, epilepsy, convulsion, motoricity problems, amnesia, cerebrovascular diseases or senile dementia.

This application is a continuation of Ser. No. 08/473,066 filed Jun. 7, 1995 now U.S. Pat. No. 5,731,331.

The present invention relates to new 4-aryltetra-hydropyridines and 4-arylpiperidinols linked to alkyl-azoles of general formula (I)

and to their physiologically acceptable salts, to the processes for their preparation, to their application as medicaments and to the pharmaceutical compositions which contain them.

The compounds which are the subjects of the invention can also be used in the pharmaceutical industry as intermediates and for the preparation of medicaments.

These compounds possess a powerful affinity for sigma and/or 5-HT_(1A) receptors and are therefore potentially useful in the treatment of certain psychic and neurological disorders of human beings and other mammals.

Phenomena exist which involve sigma receptors in the treatment of psychosis. Many atypical antipsychotics, such as rimcazole (Schwarcz, G. et al., Drug Dev. Res., 1985, 5, 387), remoxipride (Wadworth, A. B. et al., Drugs 1990, 40, 863) or thiospirone (Jain, A. K. et al., Int. Clin. Psychopharmacol. 1987, 2, 129), show a significant affinity for sigma receptors.

Moreover, studies of the biology and function of sigma receptors indicate that ligands for the sigma receptor can be effective in the treatment of certain motor disorders, in particular Huntington's chorea, dystonia and Tourette's syndrome. The presence of sigma receptors in the substantia nigra makes it possible to use them in the treatment of Parkinson's disease (Walker, J. M. et al., Pharmacological Reviews, 1990, 42, 355).

Certain ligands for sigma receptors are involved in the modulation of the effects produced by the intervention of the NMDA receptor and act as antiischemic agents in in vivo tests (Rao, T. S. et al., Molecular Pharmacology, 1990, 37, 978), with the possibility of use as neuroprotectors and in the treatment of epilepsy and of convulsion (Kaiser C., Neurotransmissions VII, 1991).

It has been said that ligands for sigma receptors exhibit antiamnesic effects in animal models (Early et al., Brain Research, 1991, 546, 281).

Sigma ligands influence the levels of acetylcholine in animal models (Matsuno et al., Brain Research 1992, 575, 315) and can consequently be used in the treatment of senile dementia, for example of Alzheimer type.

Ligands for 5-HT_(1A) receptors, in particular agonists or partial agonists for 5-HT_(1A), show a proven anxiolytic and antidepressant activity (Glitz, D. A., Drugs, 1991, 41, 11).

Consequently, agents having a powerful affinity for sigma and/or 5-HT_(1A) receptors can be used in one or a number of the treatments indicated.

Examples of 4-aryl-1,2,3,6-tetrahydropyridines and of 4-aryl-4-hydroxypiperidines are found in the bibliography; however, compounds in which these sub-structures are joined to the nitrogen of an azole ring by means of an unsubstituted alkyl chain are not found to be described:

Davis L. Temple et al., U.S. Pat. No. 4,320,131; 16 March 1982.

Richard A. Glennon et al., J. Med. Chem., 1991, 34, 3360-65.

Jean-Luc Malleron et al., J. Med. Chem., 1991, 34; 8, 2477-83.

Henning Böttcher et al., J. Med. Chem., 1992, 35, 4020-26.

Zhuihua Sui et al., Synthesis, 1993, 803-8.

David I. Schuster et al., J. Med. Chem., 1993, 36, 3923-28.

David J. Wustrow et al., BioMed. Chem. Lett., 1993, 3, 277-80.

Shimazaki Norihiko et al., Can. Pat. App., CA 2053475 AA.

The Inventors have previously described a series of N-alkylazoles joined to the nitrogen of various heterocycles which are useful as non-benzodiazepine agents in the treatment of anxiety (European Patents No. EP 382637, EP 497659 and EP 502786) and in the treatment of other behavioral disorders (European Patents EP 429360 and EP 497658). Descriptions are given in the cited patents of the compounds of general formula (I) in which A represents, in all cases, a nitrogen atom and it consequently concerns a piperazine ring. In the present invention, the piperazine ring is replaced by a piperidine or a tetrahydropyridine.

The compounds which are the subjects of the invention correspond to the general formula (I)

in which

R₁, R₂ and R₃, which are identical or different, each represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, an aryl or substituted aryl radical or an alkoxyl radical. Moreover, two adjacent radicals can form a saturated or aromatic ring.

A represents a carbon atom and the dotted line represents an additional bond or else A represents a carbon atom bonded to a hydroxyl group (C—OH) and the dotted line represents the absence of an additional bond.

n can have values ranging from 2 to 6

Z₁ represents a nitrogen atom or a substituted carbon atom which can be represented by C—R₄

Z₂ represents a nitrogen atom or a substituted carbon atom which can be represented by C—R₅

Z₄ represents a nitrogen atom or a substituted carbon atom which can be represented by C—R₇

R₄, R₅, R₆ and R₇, which are identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a hydroxyl radical, an alkoxyl radical, a carboxyl radical, a carboxamide radical, an alkyl carboxylate radical or an aryl or substituted aryl radical or else two adjacent radicals can form part of another ring, which may or may not be aromatic.

The invention also relates to the physiologically acceptable salts of the compounds of general formula (I), in particular the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids and of alkane-, cycloalkane- or arenesulfonic acids.

The new derivatives of general formula (I) can be prepared according to the following processes:

Process A:

By reaction of a spiran derivative of general formula (II)

in which

R₁, R₂, R₃ and A have the meaning indicated above, m can have values ranging from 0 to 4 and X represents a leaving group, such as chloro, bromo, mesyloxy or tosyloxy,

with a nitrogenous heterocycle of general formula (III)

in which

Z₁, Z₂, Z₄ and R₆ have the meaning indicated above.

The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene or an aliphatic hydrocarbon such as hexane or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.

The reaction temperature varies between room temperature and the reflux temperature of the solvent used.

The reaction times vary between 1 and 24 hours.

Process B:

By simultaneous “one pot” reaction between a derivative of general formula (IV), an alkylating agent of general formula (V) and a nitrogenous heterocycle of general formula (III).

where

R₁, R₂, R₃, A, X, n, Z₁, Z₂, Z₄ and R₆ have the meaning given above.

The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene or an aliphatic hydrocarbon such as hexane or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.

The reaction temperature varies between room temperature and the ref lux temperature of the solvent used.

The reaction times vary between 1 and 24 hours.

Process C:

The preparation of the compounds of general formula (I) can be carried out by reaction, under alkylation conditions, of the amines of general formula (IV)

in which

R₁, R₂, R₃ and A have the meaning given above, with compounds of general formula (VI)

in which

X, n, Z₁, Z₂, Z₄ and R₆ have the meaning indicated above.

The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene or an aliphatic hydrocarbon such as hexane or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.

The reaction temperature varies between room temperature and the ref lux temperature of the solvent used.

The reaction times vary between 1 and 24 hours.

Process D:

The compounds of general formula (I) can be prepared by reaction, under alkylation conditions, of a compound of general formula (VII)

in which

R₁, R₂, R₃, n and A have the meaning indicated above, with a nitrogenous heterocycle of general formula (III)

in which

Z₁, Z₂, Z₄ and R₆ have the meaning given above.

The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene or an aliphatic hydrocarbon such as hexane or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.

The reaction temperature varies between room temperature and the ref lux temperature of the solvent used.

The reaction times vary between 1 and 24 hours.

Process E:

By dehydration of compounds of general formula

in which

R₁, R₂, R₃, n, Z₁, Z₂, Z₄ and R₆ have the meaning indicated above, A represents a carbon atom linked to a hydroxyl group (C—OH) and the dotted line represents the absence of any additional bond.

The reaction is carried out in acid medium, such as, for example, hydrochloric acid, trifluoroacetic acid, sulfuric acid or phosphoric acid, or by treatment with thionyl chloride in benzene.

The reaction temperature varies between room temperature and 180° C.

The reaction times vary between 1 and 14 hours.

Process F:

By addition of organometallic reagents, for example phenyllithium or phenylmagnesium bromide, to compounds of general formula (VIII)

in which

n, Z₁, Z₂, Z₄ and R₆ have the meaning given above.

The reaction is carried out in a solution of an inert solvent, generally an ether such as, for example, dimethoxyethane, tetrahydrofuran or ethyl ether.

The reaction temperature varies between room temperature and the reflux temperature of the solvent used.

The reaction times vary between 5 minutes and 24 hours.

Process G:

By reduction of the carbonyl of the amide group of compounds of general formula (IX)

in which

R₁, R₂, R₃, A, n, Z₁, Z₂, Z₄ and R₆ have the meaning indicated above.

The reaction is preferably carried out in an inert organic solvent, such as ethyl ether or tetrahydrofuran, with reducing agents such as LiAlH₄, AlH₃ or diborane.

The reaction temperature varies between room temperature and the reflux temperature of the solvent used.

The reaction times vary between 5 minutes and 24 hours.

Process H:

The corresponding salt is obtained by reaction of a compound of general formula (I) with a nontoxic inorganic or organic acid in a suitable solvent, which can be, for example, an alcohol such as methanol, ethanol or any one of the propanols or butanols, an ester such as ethyl acetate or a nitrile such as acetonitrile, and by using conventional techniques for precipitation, crystallization, and the like.

The inorganic acid is chosen, inter alia, from hydrochloric, hydrobromic, sulfuric and phosphoric acids and the organic acid is chosen from mono-, di- or tricarboxylic acids, such as, for example, acetic, lactic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, and alkane-, cycloalkane- or arenesulfonic acids.

The mono- or disalts of the acid can be formed and these salts can be in the anhydrous or hydrated form.

The invention is made clearer by the following examples, given simply by way of information, it being understood that they can in no way limit the specific conditions of the process nor the scope of the invention.

PROCESS A EXAMPLE 1 Preparation of 4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidyl)butyl]-1H-pyrazole.

A mixture of 15.0 g (48 mmol) of 8-hydroxy-8-phenyl-5-azoniaspiro[4,5]decane, 5.4 g (53 mmol) of 4-chloropyrazole and 13.2 g of potassium carbonate in 200 ml of dimethylformamide is heated at reflux for 20 hours. Evaporation to dryness is then carried out at reduced pressure, the residue is redissolved in chloroform and washing is carried out repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporation is carried out at reduced pressure, a crude product being obtained which is suspended in ethyl ether, which is filtered while cold and which is washed with ethyl ether. 12.4 g (37.1 mmol) of 4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidyl)butyl)-1H-pyrazole are obtained.

The melting point and the spectroscopic data for the identification of this product are provided in Table I.

PROCESS B EXAMPLE 7 Preparation of 4-chloro-1-[4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidyl]butyl]-1H-pyrazole.

A mixture of 8.6 g (35 mol) of 4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidine, 7.68 g of 1,4-di-bromobutane and 13.8 g of potassium carbonate in 100 ml of dimethylformamide is heated at reflux for 4 hours. 3.59 g (35 mmol) of 4-chloropyrazole are then added and the reaction mixture is maintained at reflux for 14 hours. Evaporation to dryness is then carried out at reduced pressure, the residue is redissolved in chloroform and washing is carried out repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporated at reduced pressure, a crude product being obtained which is purified by chromatography on silica gel. 9.7 g (24.2 mmol) of 4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidyl]butyl}-1H-pyrazole are obtained.

The spectroscopic data for the identification of this product are found in Table I.

PROCESS C EXAMPLE 14a Preparation of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]indole.

A mixture of 4.8 g (30 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine, 6.22 g of 1-(4-chlorobutyl)indole and 8.3 g of potassium carbonate in 100 ml of dimethylformamide is heated at 90° C. for 3 hours. Evaporation to dryness is then carried out at reduced pressure, the residue is redissolved in chloroform and washing is carried out repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporation is carried out at reduced pressure, a crude product being obtained which is purified by chromatography on silica gel. 5.7 g (17.3 mmol) of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]indole are obtained.

The spectroscopic data for the identification of this product are found in Table II.

PROCESS D EXAMPLE 21a Preparation of 4-chloro-1-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1H-pyrazole.

A solution of 2.05 g (20 mmol of 4-chloropyrazole in dimethylformamide is added dropwise to a suspension of 1.0 g of NaH in dimethylformamide. The white suspension is heated for 30 minutes at 100° C. Cooling is carried out and 4.7 g (20 mmol) of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine, dissolved in dimethylformamide, are added. Heating is carried out at reflux for 2 hours. Evaporation to dryness is then carried out and the residue is extracted with chloroform, washed with water and dried with sodium sulfate. The resulting crude product is purified by chromatography on silica gel. 5.2 g (17.2 mmol) of 4-chloro-1-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1H-pyrazole are obtained.

The spectroscopic data for the identification of this product are provided in Table II.

PROCESS E EXAMPLE 2a Preparation of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-benzimidazole.

A solution of 13.4 g (38.2 mmol) of 1-[4-(4-hydroxy-4-phenyl-1-piperidyl)butyl]-1H-benzimidazole, 150 ml of concentrated HCl and 75 ml of ethanol is heated at reflux for 6 hours. The ethanol is then evaporated and the aqueous solution is cooled, basified with dilute NaOH and extracted with chloroform. The organic phase is dried with anhydrous sodium sulfate and evaporated at reduced pressure, a crude product being obtained which is purified by chromatography on silica gel. 9.1 g (27.5 mmol) of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-benzimidazole are obtained.

The melting point and the spectroscopic data for the identification of this product are provided in Table II.

PROCESS F EXAMPLE 11 Preparation of 4,5-dichloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperidyl]butyl}-2-methyl-1H-imidazole.

A solution of 1.0 g (3.3 mmol) of 4,5-dichloro-2-methyl-1-(4-(4-oxo-1-piperidyl)butyl]-1H-imidazole in 10 ml of anhydrous tetrahydrofuran is added to a suspension of 1.08 g (11.4 mmol) of MgCl₂ in 15 ml of anhydrous THF at −40° C. and under a nitrogen atmosphere. The mixture is stirred for 5 minutes and then, at −40° C., 6.8 ml of a 1.0M solution of 4-methylphenylmagnesium bromide are added. The resulting suspension is stirred for 15 minutes at −40° C. and for 3 hours at room temperature. An aqueous ammonium chloride solution is then added and the tetrahydrofuran is evaporated. The resulting aqueous phase is extracted with chloroform. The chloroform phase is washed with water, dried with anhydrous sodium sulfate and evaporated to dryness, a crude product being obtained which is purified by chromatography on silica gel, giving 1.02 g (2.6 mmol) of 4,5-dichloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperidyl]butyl}-2-methyl-1H-imidazole.

The spectroscopic data for the identification of this product are found in Table I.

PROCESS G EXAMPLE 16a Preparation of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-pyrazole.

2.0 g of LiAlH₄ are added to a solution of 3.3 g (10 mmol) of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-3-oxobutyl]-1H-pyrazole in 25 ml of THF. The resulting mixture is refluxed for 2 hours. The excess LiAlH₄ is destroyed by addition of concentrated NaOH and water. The inorganic salts are filtered off and the THF is evaporated under vacuum, giving 2.6 g (8.2 mmol) of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-pyrazole.

The melting point and the spectroscopic data for the identification of this product are found in Table II.

PROCESS H EXAMPLE 11a Preparation of the hydrochloride of 4,5-dichloro-2-methyl-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-imidazole.

2.5 ml of an 8.4N hydrochloric acid/ethanol solution are added to a solution, cooled in an ice bath, of 7.4 g (20.3 mmol) of 4,5-dichloro-2-methyl-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-imidazole in 15 ml of absolute ethanol. After a few minutes, a precipitate appears which is filtered, washed with cold ethanol and dried, 7.7 g (19.2 mmol) of 4,5-dichloro-2-methyl-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-butyl]-1H-imidazole hydrochloride being obtained.

The melting point and the spectroscopic data for the identification of this product are found in Table II.

TABLE I

Ex R₁ R₂ R₃ R₄ R₅ Z₁ Z₂ R₆ Z₄ n IR cm⁻¹ ¹H NMR (300 MHz), δ (solvent) M.p. 1 H H H H H N CH Cl CH 4 102-103° C. 3364 (b.a., OH), 1.56 (quin, J=7.1Hz, 2H); 1.65 (b.a., 1H); 1.76 (d, J=12.4Hz, 2950, 2810, 1375, 2H); 1.90 (quin, J=7.6Hz, 2H); 2.20 (m, 2H); 2.40-2.55 1130, 991, 969, (a.c., 4H); 2.83 (d, J=9.5Hz, 2H); 4.11 (t, J=7Hz, 2H); 760, 696, 605 7.21-7.42 (a.c., 5H); 7.52 (d, J=8.5Hz, 2H) (CDCl₃) KBr 2 H H H H H C═CH₃ N Cl CCl 4  86-89° C. 3196 (b.a., OH), 1.59 (m, J=5.3 J′=6.6, 2H); 1.70-1.32 (a.c., 4H); 2.16 2951, 2924, 2824, (d, t, J=13.0Hz J′=4.4Hz, 2H); 2.37 (s, 3H); 2.41-2.55 (a.c., 1406, 1247, 1146, 5H); 2.79 (d, J=11.3Hz, 2H); 3.88 (t, J=7.5Hz, 2H); 7.27 762, 703 (t, J=7.2Hz, 1H); 7.36 (t, J=7.6Hz, 2H); 7.51 (d, J=7.3Hz, KBr 2H) (CDCl₃) 3 H H H H H CH N CH═ CH—CH═ CH—C 4 122-123° C. 3180 (b.a., OH), 1.51 (quin, J=7.4Hz, 2H); 1.73 (d, J=12.7Hz, 2H); 1.87 2929, 2818, 1496, (quin, J=7.6Hz, 2H); 2.10 (dt, J=12.9Hz J′=4.1Hz, 2H); 1467, 1459, 1445, 2.36-2.50 (a.c., 4H); 2.70 (d, J=11.2Hz, 2H); 3.25 (b.a., 1286, 1219, 1143, 1H); 4.12 (t, J=7.1Hz, 2H); 7.21-7.40 (a.c., 6H); 7.51 769, 743, 707 (d, J=8.3Hz, 2H); 7.70-7.75 (a.c., 2H) (CDCl₃) KBr 4 H H H H H CH N H N 4 123° C. 3180 (b.a., OH), 1.45 (quin, J=7.5Hz, 2H); 1.69 (d, J=12.9Hz, 2H); 1.85 2949, 2919, 2838, (quin, J=7.5Hz, 2H); 2.07 (dt, J=13.0Hz J′=4.1Hz, 2H); 1276, 1145, 1135, 2.33-2.45 (a.c., 4H); 2.69 (d, J=11.2Hz, 2H); 2.93 (b.a., 1006, 770, 707, 1H); 4.10 (t, J=6.9Hz, 2H); 7.18 (t, J=7Hz, 1H); 7.27 676 (t, J=7.8Hz, 2H); 7.46 (d, J=8.3Hz, 2H); 7.80 (s, 1H); 7.91 KBr (s, 1H) (CDCl₃) 5 H H Cl H H N CH Cl CH 4 106° C. 3145 (b.a., OH), 1.47 (quin, J=7.5Hz, 2H); 1.69 (d, J=11.9Hz, 2H); 1.84 2947, 2918, 2834, (quin, J=7.6Hz, 2H); 2.05 (dt, J=13Hz, J′=4.4Hz, 2H); 1318, 1147, 1083, 2.34-2.50 (a.c., 5H); 2.72 (d, J=11.2Hz, 2H); 4.05 1112, 990, 817, (t, J=7.0Hz, 2H); 7.29 (syst. AB, J=8.6Hz, 2H); 7.36 612 (s, 2H); 7.42 ( syst. AB, J=8.6Hz, 2H) (CDCl₃) KBr 6 H H Cl H H C═CH₃ N Cl CCl 4 oil 3340 (b.a., OH), 1.54 (m, 2H); 1.67-1.78 (a.c., 4H); 2.06 (dt, J=13Hz, 2946, 2820, 1537, J′=4.2Hz, 2H); 2.32 (s, 3H); 2.38-2.45 (a.c., 5H); 2.73 1492, 1471, 1406, (d, J=11.2Hz, 2H); 3.86 (t, J=7.3Hz, 2H); 7.28 ; syst AB, 1376, 1247, 1135, J=8.6Hz, 2H); 7.43 (syst AB, J=8.6Hz, 2H) (CDCl₃) 1094, 1013, 828, 755 film 7 H CF₃ H H H N CH Cl CH 4 oil 3360 (b.a., OH), 1.48 (quin, J=7.6Hz, 2H); 1.71 (d, J=12.5Hz, 2H); 1.85 2948, 2823, 1438, (quin, J=7.6Hz, 2H); 2.06-2.21 (a.c., 3H); 2.36-2.43 1378, 1330, 1212, (a.c., 4H); 2.76 (d, J=11.5Hz, 2H); 4.06 (t, J=7.1Hz, 2H); 1165, 1124, 1047, 7.35 (s, 2H); 7.43-7.51 (a.c., 2H); 7.66 (d, J=7.5Hz, 1H); 972, 804, 704 7.79 (s, 1H) (CDCl₃) film 8 H CF₃ H H H C═CH₃ N Cl CCl 4 oil 3340 (b.a., OH), 1.57 (quin, J=7.5Hz, 2H); 1.70-1.80 (a.c., 4H); 2.15 (dt, 2948, 2823, 1408, J=12.9Hz J′=3.6Hz, 2H); 2.35 (s, 3H); 2.40-2.52 (a.c., 4H); 1330, 1165, 1126, 2.80 (d, J=11.7Hz, 2H); 3.88 (t, J=7.0Hz, 2H); 7.42-7.57 1075, 789, 763, (a.c., 2H); 7.69 (d, J=7.5Hz, 1H); 7.82 (s, 1H) (CDCl₃) 704 film 9 H H F H H C═CH₃ N Cl CCl 4 oil 3330 (b.a., OH), 1.58 (m, 2H); 1.64-1.81 (a.c., 4H); 2.14 (dt, J=12.9Hz 2946, 2818, 1509, J′=3.6Hz 2H); 2.32 (s, 3H); 2.43-2.60 (a.c., 4H); 2.84 1406, 1247, 1222, (d, J=11Hz, 2H); 3.87 (t, J=7.1Hz, 2H); 4,18 (b.a., 1H); 1160, 835 7.01 (t, J=8.8Hz, 2H); 7.46 (dd, J=8.8Hz J′=5.2Hz, 2H) film (CDCl₃) 10 H H H H H CH CH CH═ CH—CH═ CH—C 4 109-111° C. 3190 (b.a., OH), 1.57 (m, 2H); 1.73 (d, J=14Hz, 2H); 1.80 (b.a., 1H); 1.90 2956, 2823, 1461, (m, 2H); 2.13 (dt, J=13Hz J′=4Hz, 2H); 2.32-2.46 (a.c., 4H); 1446, 1319, 1303, 2.76 (d, J=11.3Hz, 2H); 4.16 (t, J=7.1Hz, 2H); 6.50 1218, 1142, 738, (d, J=3.1Hz, 1H); 7.05-7.14 (a.c., 2H); 7.18-7.40 (a.c., 5H); 703 7.50 (d, J=7.8Hz, 2H); 7.00 (d, J=7.3Hz, 1H) (CDCl₃) KBr 11 H H CH₃ H H C═CH₃ N Cl CCl 4 oil 3360 (b.a., OH) 1.53 (m, 2H); 1.66-1.84 (a.c., 4H); 2.09 (dt, J=12.9Hz, 2946, 2818, 1535, J′=3.6Hz, 2H); 2.33 (s, 3H); 2.36 (s, 3H); 2.39-2.50 1471, 1406, 1376, (a.c., 4H); 2.77 (d, J=11.2Hz, 2H); 3.87 (t, J=7.0Hz, 2H); 1247, 1134, 817, 7.15 (syst AB, J=7.8Hz, 2H); 7.33 (syst AB, J=7.8Hz, 755 2H) (CDCl₃) film 12 H H H H H N CH H CH 4  89-91° C. 3137 (b.a., OH) 1.51 (quin, J=7.6Hz, 2H); 1.73 (d, J=12.3Hz, 2H); 1.89 2947, 2532, 1396, (quin, J=7.6Hz, 2H); 2.00-2.20 (a.c., 3H); 2.35-2.45 1378, 1119, 1046, (a.c., 4H); 2.76 (d, J=10.2Hz, 2H); 4.13 (t, J=7.1Hz, 2H); 756, 697 6.21 (s, 1H); 7.21 (m, 1H); 7.30-7.37 (a.c., 3H); 7.44-7.52 KBr (a.c., 3H) (CDCl₃) 13 H H H H H N CH CH═ CH—CH═ CH—C 4 107-109° C. 3311 (b.a., OH) 1.53 (m, 2H); 1.71 (d, J=12.2Hz, 2H); 1.95 (m, 2H); 2.10 2953, 2803, 1465, (m, 2H); 2.29 (b.a., 1H); 2.35-2.47 (a.c., 4H); 2.71 (d, 2H); 1375, 1133, 1117, 4.39 (t, J=7.1Hz, 2H); 7.13 (t, 1H); 7.22-7.44 (a.c., 5H); 1043, 1017, 761, 7.50 (d, J=8Hz, 2H); 7.71 (d, J=8.3Hz, 1H); 7.95 (s, 1H) 744, 704 KBr (CDCl₃) 14 H H H H H N C═CH═ CH—CH═ CH CH 4 120-122° C. 3295 (b.a., OH) 1.58 (m, 2H); 1.73 (d, J=13.5Hz, 2H); 1.90-2.20 (a.c., 5H); 2946, 2817, 1377, 2.38-2.47 (a.c., 4H); 2.75 (d, J=10.5Hz, 2H); 4.42 1126, 786, 735, (t, J=6.6Hz, 2H); 7.06 (t, J=7.5Hz, 1H); 7.22-7.37 (a.c., 4H); 700 7.49 (d, J=7.8Hz, 2H); 7.61-7.71 (a.c., 2H); 7.90 (s, 1H) KBr (CDCl₃) 15 H H CH₃ H H N CH Cl CH 4  81-82° C. 3122 (b.a., OH) 1.51 (quin, J=7.6Hz, 2H); 1.73 (d, J=11.7Hz, 2H); 1.87 2936, 1475, (quin, J=7.6Hz, 2H); 2.12 (dt, J=12.8Hz J′=4.4Hz, 2H); 1434, 1378, 1319, 2.33 (s, 3H); 2.35-2.48 (a.c., 5H); 2.74 (d, J=11.2Hz, 2H); 989, 973, 814 4.07 (t, J=7.1Hz, 2H); 7.15 (d, J=8Hz, 2H); 7.25-7.40 KBr (a.c., 4H) (CDCl₃) 16 H H CH₃O H H N CH Cl CH 4 122-123° C. 3190 (b.a., OH) 1.49 (quin, J=7.6Hz, 2H); 1.72 (d, J=11.8Hz, 2H); 1.84 2954, 2923, 2827, (quin, J=7.4Hz, 2H); 2.00-2.14 (a.c. (dt+b.a.), 3H); 1509, 1314, 1243, 2.34-2.47 (a.c., 4H); 2.72 (d, J=11Hz, 2H); 3.77 (s, 3H); 1178, 971 4.05 (t, J=7.1Hz, 2H); 6.85 (d, J=9Hz, 2H); 7.24-7.42 (a.c., 4H) (CDCl₃) 17 H H H H H CPh N H CH 4 108-110° C. 3220 (b.a., OH) 1.45 (quin, J=7.6Hz, 2H); 1.68-1.82 (a.c., 4H); 2.08 (dt, J= 2944, 2817, 1473, 13.0Hz J′=4.1Hz, 2H); 2.29-2.42 (a.c., 4H); 2.51 (b.a., 1H); 1446, 1421, 1136, 2.67 (d, J=11.2Hz, 2H); 4.01 m(t, J=7.3Hz, 2H); 7.01 (s, 1H); 1046, 787, 773, 7.08 (s, 1H); 7.20-7.56 (a.c., 10H) (CDCl₃) 761, 700 film 18 H H CH₃ H H CH N CH═ CH—CH═ CH—C 4 oil 3260 (b.a., OH) 1.58 (quin, J=7.6Hz, 2H); 1.74 (d, J=12Hz, 2H); 1.82 (b.a., 2944, 2817, 1497, 1H); 1.95 (quin, J=7.6Hz, 2H); 2.11 (dt, 2H); 2.33 (s, 3H); 1459, 1381, 1287, 2.40-2.50 (a.c., 4H); 2.74 (d, J=11.5Hz, 2H); 4.20 (t, J= 1135, 1046, 817, 7.1Hz, 2H); 7.15 (d, J=8.3Hz, 2H); 7.22-7.35 (a.c., 3H); 745 7.37-7.43 (a.c., 2H); 7.79 (m, 1H); 7.87 (s, 1H) (CDCl₃) film 19 H H H H H CH N Ph CPh 4 138-139° C. 3194 (b.a., OH) 1.38 (m, 2H); 1.56 (m, 2H); 1.72 (d, J=12.4Hz, 2H); 2.09 2939, 2806, 1509, (dt, 2H); 2.25 (t, J=7.4Hz, 2H); 2.39 (m, 2H); 2.66 (m, 2H); 1446, 773, 766, 3.10 (b.a., 1H); 3.78 (t, J=7.2Hz, 2H); 7.10-7.52 (a.c., 758, 696 16H); KBr 20 CH═ CH—CH═ CH H H H N CH Cl CH 4 oil 3357 (b.a., OH), 1.44 (quin, J=7.3Hz, 2H); 1.77 (quin, J=7.5Hz, 2H); 2946, 2833, 1434, 2.15-2.30 (a.c., 5H); 2.34 (t, J=7.5Hz, 2H); 2.57 (m, 2H); 1379, 1315, 1140, 2.73 (d, J=11.3Hz, 2H); 3.99 (t, J=7.1Hz, 2H); 7.26-7.46 1123, 972, 781, (a.c., 6H); 7.73 (d, J=8.1Hz, 1H); 7.82 (m, 1H); 8.91 613 (m, 1H) (CDCl₃) KBr 21 H CH═ CH—CH═ CH H H N CH Cl CH 4 142-143° C. 3131 (b.a., OH), 1.55 (quin, J=7.5Hz, 2H); 1.70-1.97 (a.c., 5H); 2.29 2950, 2820, 1377, (dt, J=12.7Hz, J′=4.1Hz, 2H); 2.41-2.55 (a.c., 4H); 2.83 1311, 971, 829, (d, J=11.7Hz, 2H); 4.11 (t, J=7.0Hz, 2H); 7.39-7.50 761, 613 (a.c., 4H); 7.64 (dd, J=9.1Hz, J′=1.5Hz, 1H); 7.81-7.85 KBr (a.c., 3H); 7.95 (s, 1H) (CDCl₃) Salt/M.p. 22 H H H H H N CH

CH 4 137-140° C. 3347, 2944, 2810, 1562, 1492, 1376, 1127, 1094, 1002, 952, 828, 760, 699 KBr 1.56 (m, 2H); 1.74 (m, 2H); 1.80 (b.a, 1H); 1.94 (m, 2H): 2.40 (dt, J=13.1Hz, J=4.0Hz, 2H); 2.40-2.50 (a.c., 4H); 2.77 (m, 2H); 4.15 (t, J=7.0Hz, 2H); 7.25-7.40 (a.c., 7H); # 7.50 (d, J=8.3Hz, 2H); 7.61 (s, 1H); 7.72 (s, 1H) (CDCl₃) 23 H H F H H CH N CH═ CH—CH═ CH—C 4 120-122° C. 3230, 2947, 2915, 1.58 (m, 2H); 1.70 (m, 2H); 1.93 (m, 2H); 2.12 (m, 2H); 1504, 1219, 1135, 2.40-2.55 (a.c., 4H); 2.76 (m, 2H); 4.19 (t, J=7.0 Hz, 2H); 835, 746 7.02 (m, 2H); 7.26 (m, 2H); 7.30-7.50 (a.c., 3H); 7.74 (m, KBr 1H); 7.83 (s, 1H) (CDCl₃) 24 H CCF₃ H H H N CH Cl CH 4 HCl 3259, 2465, 2420, 1.62-1.84 (a.c., 6H); 2.53 (m, 2H); 3.09-3.40 (a.c., 6H); 147-148° C. 2365, 1328, 1108, 4.12 (t, J=6.8Hz, 2H); 5.76 (s, 1H); 7.51 (s, 1H); 7.52-7.82 1073 KBr (a.c., 4H); 8.02 (s, 1H); 10.96 (b.a., 1H) DMSO-d₆) 25 H H F H H N CH CH═ CH—CH═ CH—C 4 136-137° C. 3303, 2951, 2805, 1.54 (m, 2H); 1.60-1.80 (a.c., 3H); 1.97 (m, 2H); 2.06 1506, 1464, 1376, (dt, J=13.0Hz, J′=4.3Hz, 2H); 2.30-2.43 (a.c. 4H; 2.72 (m, 1218, 1162, 1118, 2H); 4.40 (t, J=7.0Hz, 2H); 6.99 (t, J=8.8Hz, 2H); 7.12 (m, 832, 741 1H); 7.32-7.47 (a.c., 4H); 7.71 (d, J=8.1Hz, 1H); 7.96 (s, KBr 1H) (CDCl₃-CD₃OD [1:1]) 26 H H F H H N C═CH═ CH—CH═ CH CH 4 148-150° C. 3325, 2950, 2923, 1.57 (m, 2H); 1.70-1.77 (a.c., 3H); 1.98-2.19 (a.c., 4H); 2812, 1509, 1377, 2.35-2.49 (a.c., 4H); 2.77 (d, J=11.2Hz, 2H); 4.45 1218, 1131, 834, (t, J=7.0Hz, 2H); 6.98-7.15 (a.c., 3H); 7.25-7.49 (a.c., 3H); 758 7.63 (d, J=8.3Hz, 1H); 7.69 (d, J=7.8Hz, 1H); 7.91 (s, 1H) KBr (CDCl₃-CD₃OD [1:1]) 27 H H F H H N C═CH═ CH—CH═ CH N 4 109-110° C. 3400, 2931, 2812, 1.47-1.80 (a.c., 4H); 1.90-2.25 (a.c., 5H); 2.30-2.55 (a.c., 1509, 1229, 1101, 4H); 2.70 (m, 2H); 4.78 (t, J=6.9Hz, 2H): 7.01 (t, J=8.7Hz, 831, 745 2H); 7.26-7.54 (a.c., 4H); 7.85 (dd, J=6.7Hz, J′=3.0Hz, 2H) KBr (CDCl₃-CD₃OD [1:1]) 28 H H F H H N N CH═ CH—CH═ CH—C 4 102-103° C. 3430, 2952, 2925, 1.45-1.80 (a.c., 4H); 1.85-2.25 (a.c., 5H); 2.25-2.55 (a.c., 1508, 1223, 1140, 4H); 2.77 (m, 2H); 4.69 (t, J=6.9Hz, 2H); 7.01 (t, J=8.7Hz, 833, 744 2H); 7.26-7.53 (a.c., 5H); 8.06 (d, J=7.3Hz, 1H) KBr (CDCl₃-CD₃OD [1:1])

TABLE II

Ex R₁ R₂ R₃ R₄ R₅ Z₁ Z₂ R₆ Z₄ n IR cm⁻¹ ¹H NMR (300 MHz), δ (solvent) M.p.  1a H H H H H N CH Cl CH 4  62-64° C. 3113, 2920, 2745, 1.56 (quin, J=7.6Hz, 2H); 1.91 (quin, J=7.6Hz, 2H); 2.47 1375, 1325, 1138, (t, J=7.4Hz, 2H); 2.58 (m, 2H); 2.65 (t, J=5.6Hz, 2H); 3.14 965, 837, 742, (m, 2H); 4.11 (t, J=7.1Hz, 2H); 6.06 (m, 1H): 7.23-7.42 688 (a.c., 7H) (CDCl₃) KBr  2a H H H H H CH N CH═ CH—CH═ CH—C 4  66-69° C. 2933, 1495, 745, 1.55 (quin, J=7.6Hz, 2H); 1.92 (quin, J=7.6Hz, 2H): 2.43 694, 665 (t, J=7.3Hz, 2H); 2.52 (m, 2H); 2.61 (t, J=5.6Hz 2H); 3.07 film (m, 2H); 4.14 (t, J=7.1Hz, 2H); 6.02 (m, 1H); 7.20-7.40 (a.c., 8H); 7.80 (m, 1H); 7.86 (s, 1H) (CDCl₃)  3a H H H H H CH N H N 4  63-64° C. 2942, 1438, 1381, 1.56 (m, 2H); 1.95 (m, 2H); 2.47 (t, J=7.1Hz, 2H); 2.56 1271, 1142, 1006, (m, 2H); 2.66 (t, J=5.3Hz, 2H); 3.11 (m, 2H); 4.19 753, 697, 681, (t, J=7.0Hz, 2H); 6.05 (s, 1H); 7.21 (m, 1H); 7.30 KBr (t, J=7.6Hz, 2H); 7.36 (d, J=7.8Hz, 2H); 7.94 (s, 1H); 8.06 (s, 1H) (CDCl₃)  4a H H Cl H H N CH Cl CH 4 103-104° C. 2939, 1493, 1436, 1.54 (m, 2H); 1.90 (m, 2H); 2.45 (t, J=7.4Hz, 2H); 2.51 1381, 1306, 1122, (m, 2H); 2.65 (t, J=5.6Hz, 2H); 3.10 (m, 2H); 4.10 1097, 973, 843, (t, J=7.0Hz, 2H); 6.03 (m, 1H); 7.26 (syst AB, J=8.6Hz. 824, 730 2H); 7.29 (syst AB, J=8.6Hz, 2H); 7.37 (s, 1H); 7.41 KBr (s, 1H) (CDCl₃)  5a H H Cl H H C═CH₃ N Cl CCl 4 119-120° C. 2922, 1531, 1494, 1.59 (m, 2H); 1.76 (m, 2H); 2.36 (s, 3H); 2.42-2.53 (a.c., 1469, 1403, 1380, 4H); 2.67 (t, J=5.3Hz, 2H); 3.12 (m, 2H); 3.88 (t, J=7.4Hz, 1136, 1245, 1094, 2H); 6.04 (m, 1H); 7.27 (syst AB, J=9.1Hz, 2H); 7.30 1010 (syst AB, J=9.1Hz, 2H) (CDCl₃) KBr  6a H CF₃ H H H N CH Cl CH 4 oil 2944, 1434, 1375, 1.53, (quin, J=7.5Hz, 2H); 1.89 (quin, J=7.7Hz, 2H); 2.45 1331, 1247, 1165, (t, J=7.3Hz, 2H); 2.54 (m, 2H); 2.66 (t, J=5.5Hz, 2H); 3.10 1126, 1076, 972, (m, 2H); 4.08 (t, J=7.1Hz, 2H); 6.10 (m, 1H); 7.35-7.56 800, 698 (a.c., 5H); 7.59 (s, 1H) (CDCl₃) film  7a H CF₃ H H H C═CH₃ N Cl CCl 4 oil 2931, 2815, 1533, 1.62 (quin, J=6.6Hz, 2H); 1.77 (quin, J=7.6Hz, 2H); 2.37 1405, 1331, 1246, (s, 3H); 2.51 (t, J=7.2Hz, 2H); 2.60 (m, 2H); 2.71 1165, 1125, 1076, (t, J=5.6Hz, 2H); 3.17 (m, 2H); 3.89 (t, J=7.3Hz, 2H); 6.14 797, 699 (m, 1H); 7.40-7.50 (a.c., 2H); 7.55 (d, J=7.5Hz, 1H); 7.62 film (s, 1H) (CDCl₃)  8a H H F H H N CH Cl CH 4  86-87° C. 2936, 1512, 1378, 1.60 (quin, J=7.5Hz, 2H); 1.91 (quin, J=7.5Hz, 2H); 1326, 1229, 988, 2.50-2.82 (a.c., 4H); 2.76 (t, J=5.6Hz, 2H); 3.19 (m, 2H); 967 4.11 (t, J=6.9Hz, 2H); 5.97 (s, 1H); 6.99 (t, J=8.8Hz, 2H); KBr 7.32 (dd, J=8.8Hz J′=5.4Hz, 2H); 7.38 (s, 1H); 7.40 (s, 1H) (CDCl₃)  9a H H F H H C═CH₃ N Cl CCl 4  79-82° C. 2934, 1531, 1512, 1.59 (m, 2H); 1.76 (m, 2H); 2.37 (s, 3H); 1408, 1247, 1225, 2.48 (t, J=7.2Hz, 2H); 2.54 (m, 2H); 2.67, 99 1167, 818 (t, J=5.6 Hz, 2H); 3.12 (m, 2H); 3.89 (t, J=7.3Hz, KBr 2H); 5.99 (m, 1H); 6.99 (t, J=8.7Hz, 2H); 7.33 (dd, J=8.7Hz J′=5.4Hz, 2H) (CDCl₃) 10a H H H H H C═CH₃ N Cl CCl 4 oil 2929, 1533, 1405, 1.59 (m, 2H); 1.76 (m, 2H); 2.37 (s, 3H); 2.49 (t, J=7.3Hz, 1246, 748 2H); 2.58 (m, 2H); 2.69 (t, J=5.4Hz, 2H); 3.14 (m, 2H): film 3.89 (t, J=7.4Hz, 2H); 6.06 (m, 1H); 7.22-7.40 (a.c., 5H) (CDCl₃) 11a H H H H H C═CH₃ N Cl CCl 4 .HCl 2930, 2576, 1407, 1.69 (m, 2H); 1.81 (m, 2H); 2.35 (s, 3H); 2.71 (d, J=7.2Hz, 203-204° C. 1376, 1245, 750, 1H); 2.91 (m, 1H); 3.17 (a.c., 3H); 3.56 (m, 1H); 3.75 KBr (m, 1H); 3.90-3.97 (a.c., 3H); 6.17 (s, 1H); 7.25-7.40 (a.c., 3H); 7.47 (d, J=7.6Hz, 2H); 11.30 (b.a., 1H) DMSO-d₆ 12a H H H H H C═CH₃ N Cl CCl 4 2HCl 3569, 2941, 2692, 1.67 (m, 2H); 1.79 (m, 2H); 2.36 (s, 3H); 2.69 (d, J= 192-194° C. 2556, 1601, 1446, 18.0Hz, 1H); 2.88 (m, 1H); 3.15 (a.c., 3H); 3.54 (m, 1H); 769, 753, 698 3.72 (m, 1H); 3.85-3.98 (a.c., 3H); 6.15 (s, 1H); 7.22-7.38 KBr (a.c., 3H); 7.45 (d, J=7.3Hz, 2H); 9.93 (b.a., 1H); 11.36 (b.a., 1H) (DMSO-d₆) 13a H H F H H CH CH CH═ CH—CH═ CH—C 4 oil 2937, 1510, 1464, 1.61 (quin, J=7.7Hz, 2H); 1.93 (quin, J=7.6Hz, 2H); 1230, 1161, 816, 2.42-2.58 (a.c., 4H); 2.66 (t, J=5.6Hz, 2H); 3.11 (m, 2H); 742 4.17 (t, J=7.0Hz, 2H); 5.98 (m, 1H); 6.51 (d, J=3.9Hz, 1H); film 6.95-7.39 (a.c., 8H); 7.65 (d, J=7.8Hz, 1H) (CDCl₃) 14a H H H H H CH CH CH═ CH—CH═ CH—C 4 oil 2938, 1510, 1485, 1.63 (quin, J=7.4Hz, 2H); 1.94 (quin, J=7.4Hz, 2H); 2.49 1463, 1446, 1376, (t, J=7.6Hz, 2H); 2.60 (m, 2H); 2.69 (t, J=5.3Hz, 2H); 3.14 1336, 1315, 763, (m, 2H); 4.19 (t, J=7.1Hz, 2H); 6.08 (m, 1H); 6.53 (m, 1H); 740, 695 7.08-7.44 (a.c., 9H); 7.67 (d, J=8.1Hz, 1H) (CDCl₃) film 15a H H CH₃ H H C═CH₃ N Cl CCl 4  87-88° C. 2939, 2916, 1529, 1.59 (m, 2H); 1.75 (m, 2H); 2.32 (s, 3H); 2.36 (s. 3H); 1404, 1378, 1243, 2.47 (t, J=7.2Hz, 2H); 2.54 (m, 2H); 2.67 (t, J=5.2Hz, 2H); 1166, 1133, 1016 3.11 (m, 2H); 3.87 (t, J=7.3Hz, 2H); 6.01 (s, 1H); 7.11 film (syst AB, J=8.1Hz, 2H); 7.27 (syst AB, J=8.1Hz, 2H) (CDCl₃) 16a H H H H H N CH H CH 4  36-38° C. 2941, 1396, 748, 1.54 (quin, J=7.6Hz, 2H); 1.91 (quin, J=7.6Hz, 2H); 2.45 695 (t, J=7.6Hz, 2H); 2.55 (m, 2H); 2.65 (t, J=5.6Hz, 2H); 3.11 film (m, 2H); 4.14 (t, J=7.1Hz, 2H); 6.03 (m, 1H); 6.21 (m, 1H); 7.20-7.39 (a.c., 6H); 7.49 (m, 1H) (CDCl₃) 17a H H H H H N CH CH═ CH—CH═ CH—C 4  50-52° C. 2942, 1465, 1158, 1.61 (quin, 2H); 2.00 (quin, J=7.5Hz, 2H); 2.43-2.58 (a.c., 832, 740, 691 4H); 2.68 (m, 2H); 3.14 (s, 2H); 4.43 (t, J=6.6Hz, 2H); 6.02 KBr (s, 1H); 7.13 (t, J=7.3Hz, 1H); 7.20-7.51 (a.c., 7H); 7.73 (d, J=7.9Hz, 1H); 7.99 (s, 1H) (CDCl₃) 18a H H H H H N C═CH═ CH—CH═ CH CH 4  73-75° C. 3049, 2940, 2778, 1.60 (quin, J=7.6Hz, 2H); 2.09 (quin, J=7.4Hz, 2H); 2.48 1467, 1371, 1158, (t, J=7.4Hz, 2H); 2.55 (m, 2H); 2.66 (t, J=5.6Hz, 2H); 3.11 1143, 1131, 757, (d, J=2.9Hz, 2H); 4.45 (t, J=7.1Hz, 2H); 6.03 (s, 1H); 7.07 742, 692 (t, J=7.5Hz, 1H); 7.20-7.39 (a.c., 6H); 7.63 (d, J=4.3Hz, 1H); KBr 7.70 (d, J=8Hz, 1H); 7.91 (s, 1H) (CDCl₃) 19a H H CH₃ H H N CH Cl CH 4  72-73° C. 3115, 2938, 2740, 1.55 (quin, 2H); 1.90 (quin, J=7.5Hz, 2H); 2.33 (s, 3H); 1376, 1328, 1137, 2.46 (t, J=7.5Hz, 2H); 2.55 (m, 2H); 2.66 (t, J=6.4Hz, 2H); 986, 966, 844, 3.11 (m, 2H); 4.10 (t, J=7.0Hz, 2H); 6.01 (s, 1H): 7.12 824, 797 (syst AB, J=8Hz, 2H); 7.27 (syst AB, J=8Hz, 2H); KBr 7.37 (s, 1H); 7.41 (s, 1H) (CDCl₃) 20a H H CH₃O H H N CH Cl CH 4 104-105° C. 2923, 1533, 1405, 1.54 (quin, 2H); 1.89 (quin, J=7.6Hz, 2H); 2.44 (t, J=7.4Hz, 1379, 1246, 749 2H); 2.52 (m, 2H); 2.65 (t, J=5.3Hz, 2H); 3.10 (m, 2H); KBr 3.78 (s, 3H); 4.09 (t, J=7.0Hz, 2H); 5.95 (s, 1H); 6.84 (syst AB, J=8.5Hz, 2H); 7.31 (syst AB, J=8.5Hz, 2H); 7.36 (s, 1H); 7.40 (s, 1H) (CDCl₃) 21a H H H H H N CH Cl CH 3 oil 2948, 2923, 2811, 2.08 (quin, J=7.0Hz, 2H); 2.42 (t, J=7.0Hz, 2H); 2.58 2774, 1446, 1382, (m, 2H); 2.67 (t, J=5.6Hz, 2H); 3.13 (m, 2H); 4.17 1316, 971, 748, (t, J=6.9Hz, 2H); 6.07 (m, 1H): 7.23-7.45 (a.c., 7H) (CDCl₃) 695 film 22a H H H H H CCH₃ N Cl CCl 3 oil 2923, 1533, 1405, 1.95 (quin, J=7.2Hz, 2H); 2.39 (s, 3H); 2.46 (t, J=7.0Hz, 1379, 1246, 749 2H); 2.58 (m, 2H); 2.69 (t, J=4.9Hz, 2H); 3.13 (m, 2H); film 3.96 (t, J=7.3Hz, 2H); 6.07 (m, 1H); 7.20-7.41 (a.c., 5H) (CDCl₃) 23a H H H H H CPh N H CH 4 oil 2940, 1496, 1474, 1.51 (m, 2H); 1.81 (m, 2H); 2.40 (t, J=7.4Hz, 2H); 2.56 1445, 1379, 1275, (m, 2H); 2.63 (t, J=4.9Hz, 2H); 3.09 (m, 2H): 4.04 (t, J= 774, 698 7.2Hz, 2H); 6.03 (m, 1H); 7.03 (m, 1H); 7.13 (m, 1H); film 7.22-7.48 (a.c., 8H); 7.58 (m, 2H) (CDCl₃) 24a H H CH₃ H H CH N CH═ CH—CH═ CH—C 4  90-91° C. 2939, 2915, 1500, 1.59 (m, 2H); 1.95 (m, 2H); 2.32 (s, 3H); 2.46 (t, J= 1461, 1377, 1365, 7.3Hz, 2H); 2.53 (m, 2H); 2.63 (t, J=5.5Hz, 2H); 3.08 750 (m, 2H); 4.20 (t, J=6.95Hz, 2H); 6.00 (s, 1H); 7.11 (d, J= KBr 7.8Hz, 2H); 7.27 (a.c., 4H); 7.40 (m, 1H); 7.80 (m, 1H); 7.89 (s, 1H) (CDCl₃) 25a H H H H H CH N Ph CPh 4 100-101° C. 3130, 2939, 2770, 1.46 (quin, J=7.5Hz, 2H); 1.65 (quin, J=7.6Hz, 2H); 2.33 1600, 1506, 1443, (t, J=7.3Hz, 2H); 2.53 (m, 2H); 2.60 (m, 2H); 3.05 (m, 2H); 1259, 954, 780, 3.84 (t, J=7.2Hz, 2H); 6.02 (m, 1H); 7.05-7.50 (a.c., 15H); 774, 750, 696, 7.61 (s, 1H) (CDCl₃) 649 KBr 26a CH═ CH—CH═ CH H H H N CH Cl CH 4 oil 3057, 3043, 2942, 1.61 (quin, J=7.5Hz, 2H); 1.95 (quin, J=7.6Hz, 2H); 2806, 2768, 3378, 2.51-2.57 (a.c., 4H); 2.76 (t, J=5.6Hz, 2H); 3.20 (m, 2H); 1365, 971, 801, 4.14 (t, J=7.1Hz, 2H); 5.74 (m, 1H); 7.26-7.50 (a.c., 6H); 778 7.75 (d, J=8Hz, 1H); 7.84 (m, 1H); 8.02 (m, 1H); film (CDCl₃) 27a H CH═ CH—CH═ CH H H N CH Cl CH 4  95-96° C. 3111, 2920, 2806, 1.57 (m, 2H); 1.92 (m, 2H); 2.48 (m, 2H); 2,71 1374, 1326, 966, (a.c., 4H); 3.18 (m, 2H); 4.11 (m, 2H); 6.22 (m, 1H); 826, 749, 622, 7.38-7.50 (a.c., 4H); 7.61 (m, 1H); 7.75-7.84 (a.c., 4H) KBr (CDCl₃) Salt/M.p. 28a H H F H H CH N CH═CH—CH═CH—C 2 135-136° C. 3050, 2920, 2780, 2.54 (m, 2H); 2.74 (t, J=5.6Hz, 2H); 2.92 (t, J=6.7Hz, 2H); 135-136° C. 2760, 1510, 1492, 3.24 (m, 2H); 4.35 (t, J=6.7Hz, 2H); 5.98 (m, 1H); 7.00 1459, 1224, 1202, (t, J=8.7Hz, 2H); 7.26-7.40 (a.c., 4H); 7.42 (m, 1H); 7.81 1161, 771, 751 (m, 1H); 8.01 (s, 1H) (CDCl₃) KBr 29a H H H H H CH N CH═ CH—CH═ CH—C 4 HCl 2940, 2488, 1500, 1.70-1.90 (a.c., 4H); 2.78 (m, 2H); 3.17 (m, 2H); 177-178° C. 1420, 1390, 742 3.20-3.50 (b.a., 2H); 3.79 (m, 2H); 4.30 (t, J=6.6Hz, 2H); KBr 6.15 (s, 1H): 7.17-7.40 (a.c., 5H); 7.45 (d, J=7.3Hz, 2H); 7.65 (m, 2H); 8.35 (s, 1H) (DMSO-d₆) 30a H H F H H CH N CH═ CH—CH═ CH—C 4 106-108° C. 2942, 1512, 1498, 1.59 (quin, J=7.5Hz, 2H); 1.96 (quin, J=7.5Hz, 2H); 2.40- 1460, 1376, 1221, 2.50 (a.c., 4H); 2.63 (t, J=5.5Hz, 2H); 3.09 (m, 2H); 4.21 756 (t, J=7.1Hz, 2H); 5.97 (m, 1H): 6.98 (t, J=8.1Hz, 2H); KBr 7.20-7.35 (a.c., 4H); 7.40 (m, 1H); 7.80 (m, 1H); 7.89 (s, 1H) (CDCl₃) 31a H H F H H CH N CH═ CH—CH═ CH—C 4 HCl 2930, 1600, 1510, 1.70-2.00 (a.c., 4H); 2.78 (m, 2H); 3.20 (m, 2H): 3.20- 1275 3.60 (b.a., 2H); 3.81 (m, 2H); 4.38 (t, J=6.6Hz, 2H); 6.13 KBr (s, 1H); 7.19 (t, J=8.7Hz, 2H); 7.33 (m, 2H); 7.49 (m, 2H); 7.71 (d, J=7.8Hz, 1H); 7.77 (d, J=7.6Hz, 1H); 8.79 (s, 1H); 11.20 (b.a., 1H) (DMSO-d₆) 32a H CF₃ H H H CCH₂ N Cl CCl 4 HCl 2930, 2490, 1330, 1.67 (m, 2H); 1.79 (m, 2H); 2.33 (s, 3H); 2.79 (m, 1H); 205-206° C. 1243, 1164, 1119, 2.91 (m, 1H); 3.10-3.20 (a.c., 3H); 3.55 (m, 1H); 3.77 1076 (m, 1H); 3.91-4.00 (a.c., 3H); 6.33 (s, 1H); 7.58-7.80 KBr (a.c., 4H); 11.32 (b.a., 1H) (DMSO-d₆) 33a H H F H H N CH Cl CH 4 HCl 2543, 1512, 1232, 1.71-1.85 (a.c., 4H); 2.68 (m, 1H); 2.86 (m, 1H); 3.10- 191-192° C. 967, 807 3.20 (a.c., 3H); 3.55 (m, 1H); 3.72 (m, 1H); 3.90 (m, KBr 1H); 4.12 (t, J=6.5Hz, 2H); 6.14 (s, 1H); 7.20 (t, J=8.7Hz, 2H); 7.40-7.55 (a.c., 3H); 8.06 (s, 1H); 11.20 (b.a., 1H) (DMSO-d₆) 34a H H H H H N CH CH═ CH—CH═ CH—C 4 HCl 2931, 2566, 742 1.80 (m, 2H); 1.91 (m, 2H); 2.67 (m, 1H); 2.88 (m, 1H); 193-194° C. KBr 3.10-3.20 (a.c., 3H); 3.52 (m, 1H); 3.71 (m, 1H); 3.90 (m, 1H); 4.46 (t, J=6.7Hz, 2H); 6.15 (s, 1H); 7.14 (t, J=7.5Hz, 1H); 7.25-7.41 (a.c., 4H); 7.46 (d, J=8.6Hz, 2H); 7.71 (d, J=8.6Hz, 1H); 7.75 (d, J=8.3Hz, 1H); 8.08 (s, 1H); 11.18 (b.a., 1H) (DMSO-d₆) 35a H H F H H CCH₃ N Cl CCl 4 HCl 2930, 2590, 1512, 1.67 (m, 2H); 1.79 (m, 2H); 2.33 (s, 3H); 2.67 (m, 1H); 160-161° C. 1409, 1241, 827, 2.90 (m, 1H); 3.10-3.25 (a.c., 3H); 3.54 (m, 1H); 3.72 KBr (m, 1H); 3.85-3.98 (a.c., 3H); 6.13 (s, 1H); 7.19 (m, 2H); 7.50 (m, 2H); 11.28 (b.a., 1H) (DMSO-d₆) 36a H H H H H N CH

CH 4 HCl 198-199° C. 2472, 1560, 1450, 1095, 955, 810, 745 KBr 1.77 (m, 2H); 1.87 (m, 2H); 2.70 (m, 1H); 2.86 (m, 1H); 3.16 (a.c., 3H); 3.55 (m, 1H); 3.73 (m, 1H); 3.90 (m, 1H); 4.17 (t, J=6.6Hz, 2H); 6.15 (m, 1H); 7.25-7.47 (a.c., 7H); 7.59 (m, 2H); 7.90 (s, 1H); 8.27 (s, 1H); 10.91 # (b.a., 1H) (DMSO-d₆) 37a H H H H H N CH

CH 4 126-127° C. 2935, 1570, 1493, 1455, 1379, 1091, 953, 815, 746 KBr 1.60 (m, 2H); 1.97 (m, 2H); 2.48 (t, J=7.3Hz, 2H); 2.56 (m, 2H); 2.67 (t, J=5.1Hz, 2H); 3.13 (m, 2H); 4.18 (t, J=7.1Hz, 2H); 6.05 (m, 1H); 7.23-7.40 (a.c., 9H); 7.61 (s, 1H); 7.74 (s, 1H) (CDCl₃) 38a H H F H H N N H N 4 HCl 3450, 2429, 2707, 1.74 (m, 2H); 1.86 (m, 2H); 2.68 (m, 1H); 2.84 (m, 1H); 166-168° C. 2593, 1512, 1437, 3.16 (a.c., 3H); 3.53 (m, 1H); 3.70 (m, 1H); 3.91 (m, 1230, 816, 626 1H); 4.27 (t, J=6.7Hz, 2H); 6.12 (s, 1H); 7.19 (t, J=8.9Hz, KBr 2H); 7.50 (dd, J=7.2Hz, J′=5.5Hz, 2H); 8.23 (s, 1H); 8.93 (s, 1H); 11.02 (b.a., 1H) (DMSO-d₆) 39a H H F H H N N H N 4 oil 2944, 2808, 2773, 1.60 (m, 2H); 1.97 (m, 2H); 2.40-2.70 (a.c., 6H); 3.12 1602, 1510, 1273, (m, 2H); 4.22 (t, J=6.9Hz, 2H); 5.99 (m, 1H); 6.98 (m, 1227, 1161, 1140, 2H); 7.35 (m, 2H); 7.95 (s, 1H); 8.07 (s, 1H) (CDCl₃) 846, 824, 681 film 40a H H F H H CCH₃ N CH═ CH—CH═ CH—C 4 oil 2932, 1512, 1456, 1.63 (m, 2H); 1.88 (m, 2H); 2.42-2.55 (a.c., 4H); 2.61 1404, 1231, 744 (s, 3H); 2.65 (t, J=5.5Hz, 2H); 3.09 (m, 2H); 4.14 film (t, J=7.3Hz, 2H); 5.97 (m, 1H); 6.99 (m, 2H); 7.19-7.35 (a.c., 5H); 7.68 (m, 1H) (CDCl₃) 41a H H F H H N CH CH═ CH—CH═ CH—C 4 oil 2932, 2805, 1511, 1.57 (m, 2H); 1.99 (m, 2H); 2.42-2.50 (a.c., 4H); 2.62 1465, 1230, 1160, (t, J=5.6Hz, 2H); 3.06 (m, 2H); 4.42 (t, J=6.9Hz, 2H); 5.95 825, 752, 741 (m, 1H); 6.97 (t, J=8.8Hz, 2H); 7.12 (m, 1H); 7.25-7.41 film (a.c., 4H); 7.71 (d, J=8Hz, 1H); 7.99 (s, 1H) (CDCl₃) 42a H H F H H N C═CH═ CH—CH═ CH CH 4 102-103° C. 2941, 1510, 1374, 1.59 (quin., J=7.0Hz, 2H); 2.09 (quin., J=7.5Hz, 2H); 1226, 1162, 806, 2.40-2.50 (a.c., 4H); 2.64 (t, J=6.2Hz, 2H); 3.10 (m, 2H); 759, 741 4.45 (t, J=7.1Hz, 2H); 5.96 (m, 1H); 6.98 (t, J=8.8Hz, 2H); KBr 7.07 (t, J=7.6Hz, 1H); 7.20-7.35 (a.c., 3H); 7.63 (d, J=8.5Hz 1H); 7.71 (d, J=8.6Hz, 1H); 7.90 (s, 1H) (CDCl₃) 43a H H F H H N C═CH═ CH—CH═ CH N 4 HCl 2574, 2482, 1510, 1.80 (m, 2H); 2.11 (quin, J=7.2Hz, 2H); 2.69 (m, 1H); 208-209° C. 1231,745 2.83 (m, 1H); 3.10-3.20 (a.c., 3H); 3.52 (m, 1H); 3.71 KBr (m, 1H); 3.88 (m, 1H); 4.80 (t, J=6.3Hz, 2H); 6.11 (s, 1H); 7.19 (m, 2H); 7.41 (m, 2H); 7.50 (m, 2H); 7.91 (m, 2H); 11.07 (b.a., 1H) (DMSO-d₆) 44a H H F H H N C═CH═ CH—CH═ CH N 4  76-77° C. 2913, 1511, 1470, 1.60 (quin, J=7.5Hz, 2H); 2.19 (quin, J=8.2Hz, 2H); 1380, 1327, 1224, 2.41-2.59 (a.c., 4H); 2.64 (t, J=5.7Hz, 2H); 3.08 (m, 2H); 1172, 1132, 851, 4.77 (t, J=7.0Hz, 2H); 5.95 (m, 1H); 6.97 (t, J=8.8Hz, 2H); 826, 757 7.25-7.40 (a.c., 4H); 7.85 (m, 2H) (CDCl₃) KBr 45a H H F H H N N CH═ CH—CH═ CH—C 4 HCl 2928, 2680, 2573, 1.81 (m, 2H); 1.99 (m, 2H); 2.67 (m, 1H); 2.84 (m, 1H); 204-205° C. 2559, 1515, 1454, 3,10-3.20 (a.c., 3H); 3.53 (m, 1H); 3.72 (m, 1H); 3.90 1272, 1242, 1224, (m. 1H); 4.76 (t, J=6.9Hz, 2H); 6.12 (s, 1H); 7.19 1166, 819, 745 (t, J=8.8Hz, 2H); 7.39 (t, J=7.6 Hz, 1H); 7.45-7.60 (a.c., KBr 3H); 7.94 (d, J=8.3Hz, 2H); 8.03 (d, J=8.3Hz, 2H); 11.04 (b.a., 1H) (DMSO-d₆) 46a H H F H H N N CH═ CH—CH═ CH—C 4  88-90° C. 2939, 1510, 1229, 1.58 (quin, J=7.5Hz, 2H); 2.07 (quin, J=7.5Hz, 2H); 1209, 1164, 744 2.40-2.50 (a.c., 4H); 2.61 (m, 2H); 3.05 (m, 2H); 4.66 KBr (t, J=7.0Hz, 2H); 5.95 (m, 1H); 6.96 (t, J=8.8Hz, 2H); 7.23-7.38 (a.c., 3H); 7.44 (m, 1H); 7.52 (m, 1H); 8.04 (d, J=8.3Hz, 1H) (CDCl₃) 47a H H Cl H H N CH Cl CH 4 HCl 3068, 2948, 1491, 1.71 (m, 2H); 1.80 (m, 2H); 2.70 (m, 1H); 2.83 (m, 1H); 172-173° C. 1445, 1320, 1308, 3.15-3.30 (a.c., 3H); 3.44 (m, 1H); 3.72 (m, 1H); 3.89 (m, 1096, 968, 809, 1H); 4.11 (t, J=6.5Hz, 2H); 6.20 (s, 1H); 7.41 (Syst. 799 AB, J_(AB)=8.8Hz, 2H); 7.48 (Syst. AB, J_(AB)=8.8Hz, 2H); 7.52 KBr (s, 1H); 8.04 (s, 1H); 10.98 (b.a., 1H) (DMSO-d₆) 48a H H H H H N CH H CH 4 HCl 2955, 2929, 2530, 1.70-1.90 (a.c., 4H); 2.69 (m, 1H); 2.89 (m, 1H); 3.10- 180-181° C. 1445, 965, 761, 3.20 (a.c., 3H); 3.53 (m, 1H); 3.70 (m, 1H); 3.91 (m, 745 1H); 4.15 (t, J=6.5Hz, 2H); 6.16 (m, 1H): 6.23 (m, 1H); KBr 7.28-7.50 (a.c., 6H); 7.78 (m, 1H); 11.26 (b.a., 1H) (DMSO-d₆) 49a H H H H H CH N H N 4 HCl 2937, 2370, 1503, 1.74 (m, 2H); 1.84 (m, 2H); 2.72 (m, 1H); 2.87 (m, 1H): 122-123° C. 1276, 1142, 774, 3.10-3.20 (a.c., 3H); 3.54 (m, 1H); 3.73 (m, 1H); 3.88 755 (m, 1H); 4.22 (t, J=6.6Hz, 2H); 6.15 (s, 1H); 7.27-7.70 KBr (a.c., 3H); 7.47 (m, 2H): 7.97 (s, 1H); 8.59 (s, 1H); 11.20 (b.a., 1H) (DMSO-d₆) 50a H H H H H CPh N H CH 4 HCl 2930, 2554, 1469, 1.62-1.78 (a.c., 4H); 2.75 (m, 2H); 3.00 (m, 2H); 3.25 170-171° C. 1459, 1444, 1278, (m, 2H); 3.69 (m, 2H); 4.08 (t, J=6.7Hz, 2H); 6.13 (s, 1075, 774, 762, 1H); 7.07 (s, 1H); 7.24-7.40 (a.c., 3H); 7.42-7.52 (a.c., 749, 732, 711, 702, 6H); 7.62 (Syst. AB, J_(AB)=7.6Hz, 2H) (DMSO-d₆) 690 KBr 51a H H H H H CH CH H CH 4 HCl 2930, 2482, 1448, 1.60-1.80 (a.c., 4H); 2.70 (m, 1H); 2.84 (m, 1H); 3.08- 197-199° C. 1280, 1090, 732 3.22 (a.c., 3H); 3.50 (m, 1H); 3.71 (m, 1H); 3.86-3.96 KBr (a.c., 3H); 5.97 (t, J=2.1Hz, 2H); 6.16 (m, 1H); 6.76 (t, J=2.1Hz, 2H); 7.25-7.50 (a.c., 5H); 10.74 (b.a., 1H) (DMSO-d₆) 52a H H H H H CH CH H CH 4  58-60° C. 2928, 1498, 1280, 1.58 (m, 2H); 1.84 (m, 2H); 2.47 (t, J=7.5Hz, 2H); 2.58 1262, 1137, 1087, (m, 2H); 2.68 (m, 2H); 3.13 (m, 2H); 3.92 (t, J=7.1Hz, 1060, 747, 723, 2H); 6.06 (m, 1H); 6.15 (t, J=2.2Hz, 2H); 6.67 (t, J=2.2Hz, 691 2H); 7.24-7.42 (a.c., 5H) (CDCl₃) KBr 53a H H H H H N CCl CH═ CH—CH═ CH—C 4 oil 2939, 1495, 1467, 1.58 (quin, J=7.6Hz, 2H); 1.99 (quin, J=7.6Hz, 2H); 2.47 1338, 745 (m, 2H); 2.55 (m, 2H); 2.65 (m, 2H); 3.10 (m, 2H); 4.36 film (t, J=7.1Hz, 2H); 6.04 (m, 1H); 7.18-7.42 (a.c., 8H); 7.67 (d, J=7.6Hz, 1H) (CDCl₃) 54a H H H H H N CCl CH═ CH—CH═ CH—C 4 HCl 3460, 2940, 2550, 1.80 (m, 2H); 1.90 (m, 2H); 2.70 (m, 1H); 2.87 (m, 1H); 164-165° C. 1338, 743 3.07-3.22 (a.c., 3H); 3.52 (m, 1H); 3.71 (m, 1H); 3.87 KBr (m, 1H); 4.43 (t, J=6.6Hz, 2H); 6.14 (s, 1H): 7.20-7.52 (a.c., 7H); 7.65 (m, 1H); 7.79 (m, 1H); 11.16 (b.a., 1H) DMSO-d₆)

BIOLOGICAL TESTS BINDING TO THE SEROTONIN RECEPTOR (5-HT_(1A))

A rat hippocampus homogenate is used, a modification of the process of S. J. Peroutka, J. of Neurochem., 47(2), 529-540 (1986) being followed. [³H]-8-OH-DPAT is used as radioligand and serotonin is used for measuring the non-specific binding. The incubation time is 15 minutes at a temperature of 37° C. The radioligand bound to the protein is separated by filtration on glass fiber filters and the radioactivity retained on the filter is determined by liquid scintillation. The inhibition constants (K_(i), nM) are calculated by non-linear regression analysis by using the EBDA/LIGAND program (Munson and Rodbard, Analytical Biochemistry, 107, 220 (1980)).

BINDING TO THE SIGMA RECEPTOR

A guinea pig brain (less the cerebellum) homogenate is used, a modification of the process of L. Radesca et al., J. Med. Chem., 34, 3058-3065 (1991) being followed. [³H]-(+)-3-PPP is used as radioligand and haloperidol is used for measuring the non-specific binding. The incubation time is 120 minutes at a temperature of 25° C. The radioligand bound to the protein is separated by filtration on glass fiber filters and the radioactivity retained on the filter is determined by liquid scintillation. The inhibition constants (K_(i), nM) are calculated by non-linear regression analysis by using the EBDA/LIGAND program (Munson and Rodbard, Analytical Biochemistry, 107, 220 (1980)).

TABLE III BINDING Sigma 5-HT_(1A) Ki % Des Ki % Des Example (nM) (10⁻⁶M) (nM) (10⁻⁶M) 1  6.6 93 2  15 90 5  6.4 94 12 6  4.3 95 1a 46 86 37 94 2a 82 78 3a 11 97 56 90 4a 11 93 199 72 5a 19 96 6.1 97 6a 91 9.0 100 7a 96 0.4 98 8a 97 90 9a 97 4.6 100 10a  40 88 1.3 100 11a  92 93 14a  94 94 15a  8.4 94 98 16a  17 95 86 BMY 14802 733

The daily dose in human medicine is between 1 milligram and 500 milligrams of product, which can be administered in one or a number of intakes. The compositions are prepared in formulae compatible with the method of administration used, such as, for example, tablets, dragées, capsules, suppositories, solutions or suspensions. These compositions are prepared by known processes and they comprise from 1 to 60% by weight of active principle (compound of general formula I) and from 40 to 99% by weight of appropriate pharmaceutical vehicle compatible with the active principle and the physical form of the composition used. By way of example, the formula of a tablet which contains a product of the invention is presented.

Example of a formula for a tablet

Example 11a 5 mg Lactose 60 mg Crystalline cellulose 25 mg Povidone K 90 5 mg Pregelatinized starch 3 mg Colloidal silicon dioxide 1 mg Magnesium stearate 1 mg Total weight 100 mg 

What is claimed is:
 1. A compound of general formula (I)

and its physiologically acceptable salts, wherein R₁, R₂ and R₃, which are identical or different, each represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a linear or branched alkyl radical, an aryl or substituted aryl radical or an alkoxyl radical, or two adjacent R₁, R₂ and R₃ together with the carbon atoms to which they are attached form an aromatic or saturated ring, A represents a carbon atom and the dotted line represents an additional bond, n can have a value ranging from 2 to 6, Z₁ represents a nitrogen atom or a substituted carbon atom which can be represented by C—R₄, Z₂ represents a nitrogen atom or a substituted carbon atom which can be represented by C—R₅, and Z₄ represents a nitrogen atom or a substituted carbon atom which can be represented by C—R₇, where R₄, R₅, R₆ and R₇, which are identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a hydroxyl radical, an alkoxyl radical, a carboxyl radical, a carboxamide radical, an alkyl carboxylate radical or an aryl or substituted aryl radical.
 2. A compound selected from the group consisting of 4-Chloro-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-pyrazole; 1-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)-butyl]-1H-1,2,4-triazole; 4-Chloro-1-{4-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-pyrazole; 4,5-Dichloro-1-{4-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-2-methyl-1H-imidazole; 4-Chloro-1-{4-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-pyrazole; 4,5-Dichloro-2-methyl-1-{4-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-imidazole; 4-Chloro-1-{4-[4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-pyrazole; 4,5-Dichloro-1- {4-[4-(4-fluorophenyl) 1,2,3,6-tetrahydro-1-pyridyl]butyl}-2-methyl-1H-imidazole; 4,5-Dichloro-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-2-methyl-1H-imidazole; 4,5-Dichloro-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-2-methyl-1H-imidazole hydrochloride; 4,5-Dichloro-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-2-methyl-1H-imidazole dihydrochloride; 1-{4-[4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}indole; 1-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]indole; 4,5-Dichloro-2-methyl-1-{4-[4-(4-methylphenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-imidazole; 1-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)-butyl]-1H-pyrazole; 1-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)-butyl]-1H-indazole; 2-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)-butyl]-2H-indazole; 4-Chloro-1- {4-[4-(4-methylphenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-pyrazole; 4-Chloro-1- {4-[4-(4-methoxyphenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-pyrazole; 4-Chloro-1-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1H-pyrazole; 4,5-Dichloro-1-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-2-methyl-1H-imidazole; 2-Phenyl-1 -[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-imidazole; 4,5-Diphenyl-1 -[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-imnidazole; 4-Chloro-1-{4-[4-(1-naphthyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-pyrazole; 4-Chloro-1-{4-[4-(2-naphthyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-pyrazole; 4,5-Dichloro-2-methyl1-{4-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-imidazole hydrochloride; 4-Chloro-1-{4-[4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-pyrazole hydrochloride; 1-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)-butyl]-1H-indazole hydrochloride; 4,5-Dichloro-1-{4-[4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-2-methyl-1H-imidazole hydrochloride; 4-(4-Chlorophenyl)-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-pyrazole hydrochloride; 4-(4-Chlorophenyl)-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-pyrazole; 1-{4-[4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-indazole; 2-{4-[4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-indazole; 2-{4-[4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-2H-benzotriazole hydrochloride; 2-{4-[4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-2H-benzotriazole; 1-{4-[4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-benzotriazole hydrochloride; 1-{4-[4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-benzotriazole; 1-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)-butyl]-1H-pyrazole hydrochloride; 1-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)-butyl]-1H-triazole hydrochloride; 2-Phenyl-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-imidazole hydrochloride; 1-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-pyrrole hydrochloride; 1-[4-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-pyrrole; 3-Chloro-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-indazole; 3-Chloro-1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-indazole hydrochloride and physiologically acceptable salts thereof.
 3. A compound selected from the group consisting of 1-{4-[4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-triazolehydrochloride, 1-{4-[4-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}-1H-triazole and physiologically acceptable salts thereof.
 4. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and at least one compound of claim 1 or its physiologically acceptable salts.
 5. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and at least one compound of claim
 2. 6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and at least one compound of claim
 3. 